9-dialkylamino-5-arylamino [a] phenoxazines



Patented Nov. 7, 1950 UNITED STATES PATENT OFFICE 9-DIALKYLAMINO- 5-ARYLAMINO [a] PHENOXAZINES No Drawing. Application August 10, 1949, Serial No. 109,626

6 Claims. 1 This invention relates to new dyestuffs of the benzophenoxazine series having the following R1=alkyl with 4 or more carbon atoms R2=H or alkyl R3=homocyclic aromatic group A=H or alkyl B=H or alkyl and their addition salts with acids which are 9 probably best represented by the following formulation B l 1 s I in which X, of course, is the anion. In the form of their salts the acids are blue dyestuffs, whereas the bases give solutions of various shades of I red. Other formulations of the salts have been proposed but the one given above corresponds best with the known characteristics of the compounds.

The compounds are dyestufis and may be used in various coloring processes, particularly difier- 4O ential tissue staining for microscopic work. Some of the compounds have therapeutic activity.

On the 9-amino group both R1 and R2 may be alkyl groups of four or more carbon atoms or 45 one of the groups may be a lower alkyl such as methyl, ethyl, propyl, or hydrogen. The alkyl groups of more than one carbon atom include the various isomeric butyl, amyl and hexyl radicals and also higher alkyl radicals such as those having 14 or more carbon atoms. In general, the compounds having from 4 to 8 carbon atoms are cheaper and easier to prepare and are economically of more interest, however, the invention is not limited to these substituents only. 55

R3 may be any homocyclic aryl group. The most important radicals are those derived from the benzene and naphthalene series, such as phenyl, tolyls, xylyls and the like. substituents, such as halogens, are also included and for some purposes are advantageous.

The invention includes derivatives of benzo- [alphenoxazine itself and also its homologs. In some cases the alkyl substituents on the benzo ring and. on one of the two oarbocyclic rings of the phenoxazine nucleus materially affect the properties of the compounds and are included within the invention. The most common alkyl substituents are, of course, methyl and ethyl, though higher substituents such as propyl, isopropyl and butyl are also included.

It is not intended to limit the product protection of the present case to any single method of preparation. Two general methods, however, are particularl useful and are included in a more limited aspect of the invention. The preferred process for most of the compounds involves two steps. First, the condensation of a para-nitrosoaniline having the required alkyl substituents with beta-naphthol or its homologs and reaction of the Q-arninobenzophenoxazine thus produced with an aryl amine. This latter reaction is a rather unusual one since the 5 hydrogen atom appears to be capable of reaction with the amino group of arylamines. The mechanism of the reaction for nuclear unsubstituted 9-aminobenzophenoxazines may be illustrated as follows:

The second method, which is particularly important for preparing some of the derivatives which are not readily produced by the first method, involves the reaction of the salt of a 2- 3 nitroso-5-alky1aminophenol with an N-aryl substituted alpha-naphthylamine. The reaction for the dibutyl compound is illustrated as follows:

This second process has the advantage that the aryl naphthylamine is used as a preformed intermediate and it is possible to use it to prepare certain compounds which are not readily prepared by the first process because of the relative inactivity of the arylamine intermediate.

As far as the ring closure step is concerned the two processes are very similar. They involve the ring closure of compounds containing at least one nitroso and hydroxy group, the only difference being that in the first process the nitroso group is on one intermediate and the hydroxy on the other, and in the second process the are on the same intermediate. The two processes may be considered as variations of essentially the same type of ring-closing process involving splitting out hydrogen and water.

The invention will be described in greater detail in conjunction with the following specific examples, the parts being by weight. For simplicity, the formulae of the final products will be shown as the addition salts with acid which is the form in which the products are usually produced initially. They are transformable into the free bases by neutralization with alkali.

EXAMPLE 1 -di-mbutylaminobenzo[a] phenomazonium nitrate Heatin is continued under reflux until no yellow spot is obtained on moist filter paper by treatment with a drop of the reaction solution.

On cooling, the Q-di-n-butylaminobenzo[a] phenoxazoniumchloride zinc chloride double salt precipitates and is recovered by filtration, the precipitate being washed with alcohol. The compound is changed into the nitrate salt, which is preferable for the second step of the reaction,

by dissolving in 100,000 parts of water and treat- 7 ing with 350 parts of concentrated nitric acid. The nitrate salt is precipitated, removed by filtra- 4 tion and washed with water. It is then dried at 50 C. and is obtained as a dark green solid.

EXAMPLE 2 9 di-namylaminobenzo a] phenoxazonium nitrate I 4-nitroso-di-n-amylaniline is prepared by the same method described in Example 1 substituting di-n-amylaniline for the di-n-butylaniline. The

procedure of Example 1 is then followed except that the 1490 parts of 4-nitroso-di-n-butylanilinehydrochloride'is replaced by 1640 parts of 4- nitroso-di-n-amylanilinehydrochloride prepared as described above. The nitrate is a solid having substantially the same color as the product of Example 1.

EXAMPLE 3 9-di-n-hexylaminobenzo[a]phenorazonium nitrate 4-nitroso di n hexylanilinehydrochloride is prepared by the process described in Example lv replacing the di-n-butylaniline with the di-nhexylaniline. The procedure of Example 1 is then followed substituting 1795 parts of the hydrochloride of 4-nitroso-di-n-hexylaniline for the 1490 parts of 4-nitroso-di-n-butylaniline hydrochloride.

EXAMPLE 4 9-ethylisobutylaminobenzo[alphenoxazoniam nitrate The 4-nitroso-ethylisobutylaniline hydrochloride is prepared. by the same method described in Example 1 substituting ethylisobutylaniline for the di-n-butylaniline. The procedure of Example 1 is then followed except that the 1490 parts of- 4-nitroso-di-n-butylaniline hydrochloride is replaced by 1330 parts of 4-nitrosoethy1isobutylaniline hydrochloride prepared as described above.

EXAMPLE 5 Q-butylpropyldminobenzo [a phenozwzoniam nitrate The 4-nitroso-butylpropy1aniline hydrochloride is prepared by the same method described in Ex-' ample 1 substituting butylpropylaniline for the di-n-butylaniline.- The procedure of Example 1 is then followed except that the 1490 parts of 4? nitroso-di-n-butylaniline hydrochloride is replaced by 1410 parts of 4-nitroso-butylpropylanilineihydrochloride prepared as described above.

7 EXAMPLE 6 9- di-n-batyZamino-I 1 -methylbenzo [a] phenoarazonium nitrate The 3-methyl-4-nitroso di-n-butylaniline hydrochloride is prepared by first treating m-toluidine with an excess of'n-butyl bromide at about C. The di-n-butyl-m-toluidine formed, after purification byv distillation; is converted to 3- methyll-nitroso-di'-n-butylaniline hydrochloride by the same method described in Example 1, substituting di-n-butyl-m-toluidine for the di-nbutylaniline. The procedure of Example 1 is then followed except thatthe 1490 parts of 4-nitrosodi-n-butylaniline hydrochloride is replaced byv 1565 parts of 3-methyl 4-nitroso-di n-butylani" line hydrochloride prepared; as described above.

5. EXAMPLE 7 phenylamino-Q- di-n-butylaminobenzo [a] phenozvazoniam nitrate 1 A mixture of 21 parts of Q-din-butylaminobenzo[a]phenoxazonium nitrate, produced as described in Example 1, 200 parts of ethyl alcohol and 14 parts of aniline is warmed until a complete solutionis obtained. The Solution is allowed to stand in an open vessel for a long time until product is crystallized out. The crystals are then collected and recrystallized from ethyl alcohol. The product consists of 8 parts of bright green prisms.

This product dissolves in ethyl alcohol to give a blue solution, the color of which changes to red upon the addition of ammonium hydroxide solution. E

EXAMPLE: 8

5 4-methylphenylamino') -9-di-n-butylaminobenzo [alphenoxazoniam nitrate EXAMPLE 9 5-(3-methylphenylwminol 9 di-n-amylamino benzo al phenozcaeoni'am nitrate "To 25 parts of 9-di-n-amylaminobenzo[alphenoxazonium nitrate, prepared as described in Example 2, are added 250 parts of ethyl alcohol. The mixture is warmed gently for a few minutes to effect at least partial solution and 16 parts of m-toluidine are then added. After stirring, the mixture is allowed to stand for a long time at room temperature in an open container. The material which precipitatesis removed by filtration and purified by treatment with ethyl alcohol.

The product gives a blue solution in ethyl alcohol, the color turning red upon the addition of an alkaline reagent.

6 EXANIPLE 10 5-(4-methylphenylamino) 9 di-n-amylamino beneo [a] phenoxaeoniam, nitrate The procedure of Example 9 is followed but the p-toluidine is replaced with m-toluidine. The product obtained has the same physical properties as that of Example 9.

EXAMPLE 11 5-(2,4 dimethylphenylamino) 9 di n amyZ The procedure of Example 9 is followed replacing the 16 parts of m-toluidine with 18 parts of ZA-xylidine. The product obtained has substantially similar properties to that of Example 9.

EXAMPLE 12 5-(2-methylphenylamino) 9 di-n-hescylaminobenzo [a] phenoa'azonium nitrate CnHQ O o isN a A mixture of 12 parts of Q-di-n-hexylamino benzoEalphenoxazonium nitrate, parts of ethyl alcohol and 8 parts or" o-toluidine is stirred at room temperature for a long timein a vessel open to the atmosphere. The solid material produced is removed and treated with alcohol for EXAMPLE 13 5-(4-methylphenylamino) 9 di-n-hemylaminobenzo [a] phenoxaeoniam nitrate CeHn I pHls N The procedure of Example 12 is followed but the p-toluidine is used instead of o-toluidine. The

. N I CaHa OHCH: NO:

A mixture of 393 parts of 9-ethylisobutylaminobenzoEalphenoxazonium nitrate, prepared as described in Example 4, 280 parts of aniline and 3000 parts of ethyl alcohol is warmed slightly to effect complete solution. A greenish-blue solution is obtained. This solution is then stirred at room temperature for a long time. After standing anadditional length of time in a vessel open to the atmosphere, the product which precipitates is collected by filtration and recrystallized from ethyl alcohol.

A solution of this product in ethyl alcohol shows a greenish-blue color which color changes to red upon the addition of an alkaline reagent.

EXAMPLE 15 (4 methylpheny larnino) 9 ethylisobutyl aminobenzo [a] phenoxazonium nitrate EXAMPLE 16 5-(1 naphthyl 9 ethylisobutylphenylaminohence [a] phenozcaapnium, nitrate N V w N: NE 0 CH-CH: N03

The procedure of Example 14 is followed but 430 parts. of alphanaphthylamine are used in place of 280 parts of aniline.

The addition of excess ammonium hydroxide solution to the blue alcoholic solution of the product, precipitates the base of the product.

8 EXAMPLE 1'! 5 -phenyZamino-9 -butylpropylaminobertz0 a] phenomaeonium nitrate ClHa N03 A mixture of 407 parts of Q-butylpropylaminobenzoEalphenoxazonium nitrate, prepared as described in Example 5, 280 parts of aniline, and 3000 parts of ethyl alcohol is stirred until a complete solution is obtained. The mixture is then allowed to stand overnight, and the dark green glistening crystalline precipitate is removed by filtration and purified by recrystallization from hot ethyl alcohol.

The product obtained in this way has a limited solubility in ethyl alcohol in which it forms a blue colored solution. Addition of an. alkaline reagent causes a change to a red color with the formation of the base of the product.

EXAMPLE 18 5- (4-methylphenylamino) -9-batylpropylaminobeneomlphenoaazonium nitrate EXAMPLE 19 5- (el-chlorophenylamino) -9-batylpropylaminobeneoial phenozcazoniam nitrate N NH-C o1 l o The procedure of Example 17 is followed except that the 280 parts of aniline is replaced with 380 parts of p-chloroaniline.

The base of this nitrate is formed by the addition of excess ammonium hydroxide solution-to a solution of the product in ethyl alcohol.

EXAMPLE 20 5 -phenylamino-9-di-n-butylamino-Z1-methylbenzoEalphenoxazonium nitrate EXAIVIPLE 21 5-phenylamino-Q-amylaminobenzo[alphenoxazomumchloride A solution is prepared of 163 parts of N-amylaniline, 500 parts of concentrated hydrochloric acid and 200 parts of water. The solution is cooled to about 5 C. and a solution of 82 parts of sodium nitrite in 150 parts of water is slowly added with stirring. After the addition is complete the stirring is continued until the reaction has gone to completion and an oil forms consisting of nitrosamino derivative. This oil is separated by decantation and dissolved in 1400 parts of diethyl ether which is then treated with an excess of a saturated ethyl alcoholic solution of hydrogen chloride. The mixture is permitted to stand until reaction is substantially complete and then is cooled to about 0 C. whereupon the p-nitroso derivative of the amylaniline separates l0 EXAMPLE 23 5-phenylamino-Q-di-n-butylaminobenzo[a] phenorazine base To 218 parts of m-aminophenol are added 300 parts of ethyl alcohol forming a dark-colored slurry. To this slurry are added 411 parts of n-butyl bromide and the whole is then heated to a gentle reflux for approximately 5 hours. After removal of alcohol and some unchanged butyl bromide by distillation, the residue is poured into water and treated with soda ash to cause separation of the aminophenol derivatives. The oil layer is taken up with ether, the ether solution is dried and the ether is finally removed by distillation leaving a residue to which is added th alcohol and unchanged butyl bromide removed from the original reaction mixture plus 137 parts of fresh butyl bromide. The resulting 7 solution is then heated to the reflux temperaout and is removed. It is added slowly to a boil- 7 EXAMPLE 2 5 -phenylami no-9-tetradecylaminobenzo [a] phenozcazonium chloride The procedure of Example 21 is followed except that 289 parts of N-tetradecylaniline are used in place of 163 parts of ll-amylaniline.

The N-tetradecylaniline with a boiling point of 204-206 C. at 6 mm. which is used here is prepared by treating aniline with tetradecyl bromide and purifying the product by distillation.

ture with stirring for approximately 22 hours, and finally alcohol and a small amount of unchanged butyl bromide are again removed by distillation.

The residue is poured into 1000 parts of water, and the mixture is made alkaline by the addi: tion of solid soda ash. The product, which is present as a water insoluble oil, is removed and purified by a vacuum distillation giving the purified product in the form of a straw-colored visoous liquid with a boiiing range of approximately 173 to 176 C. at ,6 mm. pressure. Exposure of this m-dibutylaminophenol to the atmosphere causes it to acquire a deep red color.

This aminophenol derivative is dissolved in 650 parts of alcohol and 300 parts of concentrated hydrochloric acid. The resulting solution is cooled to 5 C. and to it is added a past of 76 parts of sodium nitrite in a small amount of Water over an approximately 3 hour period with mechanical stirring, the temperature being kept below 10 (3. throughout this addition period.

After stirring the mixture an additional 1 hour, the temperature is increased to about 40 C. and the sodium chloride present removed by filtration. The solution of nitroso derivative thus obtained is then added gradually to a solution of 144 parts of N-phenylalphanaphthylamine in 1000 parts of ethyl alcohol at the boiling point with stirring. The whole is refluxed for several hours, at the end of which time an intensely bluecolored solution is obtained. This is diluted with an equal volume of ethyl alcohol and treated with an excess of concentrated aqueous ammonium hydroxide which causes precipitation of the base.

Removal of the precipitate gives the Product in the form of the base. This is soluble inethyl alcohol to give a purple colored solution. A greenish-blue solution of the chloride is obtained by the addition of hydrochloric acid to a solution of the base in alcohol.

This sam product in the form of its base may also be prepared from the nitrate salt. Thus, 5 parts of 5 phenylamino 9 di-n-butylaminobenzo[alphenoxazonium nitrate, prepared as described under Example 7, are dissolved in 600 parts of ethyl alcohol and 300 parts of water. Ten parts of concentrated aqueous ammonia are added and the mixture is warmed slightly to coagulate the precipitated base. After removing and drying the dark solid, the base is obtained which shows a melting point at about 153-154 C.

The compounds of Examples 7-22 can be prepared by the process of this example using the corresponding alkylamino nitrosophenols and arylamino alphanaphthyl amines.

EXAMPLE 24 5-pheny lamino-9-butylpropylaminobenzo[a] phenomazine base N G C 4H9/ To a solution of parts of 5-phenylamino- Q-butylpropylaminobenzo[alphenoxazonium nitrate, prepared as described under Example 17, in 600 parts of alcoholand 300 parts of Water, parts of concentrated aqueous ammonia is added. The mixture is warmed for a short time to coagulate the solid material which precipitates and the base is then removed by filtration giving a dark red-brown water insoluble solid which shows a melting point at 137138 C;

We claim:

1. As new chemical compounds, the compounds selected from the class consisting of the bases having the formula:

N N413 0 R2 wherein R1 represents an alkyl group having the formula CnH2n+1 in which 'n. is an integer selected from the group consisting of 4 to 14, inclusive, R2 is a substituent selected from the group consisting of hydrogen and an alkyl radical having the formula -CmH2m+1 in which m is an integer selected from the group consisting of 1 to 14, inclusive, R3 represents an aromatic hydrocarbon radical selected from the class consisting of the benzene and naphthalene radicals, and A represents a substituent selected from the group consisting of hydrogen and lower alkyls, and their addition salts with acids.

2. As a new chemical compound, the base having the following formula:

3. As new chemical compounds, the addition salts of the base of claim 2 with strong mineral acids.

4. As a new chemical compound, the base having the following formula: 7

5. As new chemical compounds, the addition salts of the base of claim 4 with strong mineral acids.

6. As a new chemical compound, the base having th following formula:

MOSES L. CROSSLEY. PAUL F. DREISBACH. RICHARD J. TURNER. CORRIS M. HOFMANN.

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REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Germany Jan. 25, 19 0 

1. AS NEW CHEMICAL COMPOUNDS, THE COMPOUNDS SELECTED FROM THE CLASS CONSISTING OF THE BASES HAVING THE FORMULA: 